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/HCO3 exchange activity in
tracheal epithelial cells
Departments of 1 Medicine and 2 Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati School of Medicine, Cincinnati, Ohio 45267; and 3 Department of Medicine, University of North Carolina, Chapel Hill North Carolina 27599
Thickening of airway mucus and lung
dysfunction in cystic fibrosis (CF) results, at least in part, from
abnormal secretion of Cl
and HCO3
across the tracheal epithelium. The mechanism of the defect in HCO3 secretion is ill defined; however, a lack of
apical Cl/HCO3 exchange may exist in
CF. To test this hypothesis, we examined the expression of
Cl/HCO3 exchangers in tracheal
epithelial cells exhibiting physiological features prototypical of
cystic fibrosis [CFT-1 cells, lacking a functional cystic fibrosis
transmembrane conductance regulator (CFTR)] or normal trachea (CFT-1
cells transfected with functional wild-type CFTR, termed CFT-WT). Cells
were grown on coverslips and were loaded with the pH-sensitive dye
2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein, and
intracellular pH was monitored. Cl/HCO3
exchange activity increased by ~300% in cells transfected with functional CFTR, with activities increasing from 0.034 pH/min in CFT-1
cells to 0.11 in CFT-WT cells (P < 0.001, n = 8). This activity was significantly inhibited by
DIDS. The mRNA expression of the ubiquitous basolateral AE-2
Cl/HCO3 exchanger remained unchanged.
However, mRNA encoding DRA, recently shown to be a
Cl/HCO3 exchanger (Melvin JE, Park K,
Richardson L, Schultheis PJ, and Shull GE. J Biol Chem 274:
22855-22861, 1999.) was abundantly expressed in cells expressing
functional CFTR but not in cells that lacked CFTR or that expressed
mutant CFTR. In conclusion, CFTR induces the mRNA expression of
"downregulated in adenoma" (DRA) and, as a result, upregulates the
apical Cl/HCO3 exchanger activity in
tracheal cells. We propose that the tracheal HCO3
secretion defect in patients with CF is partly due to the
downregulation of the apical Cl/HCO3
exchange activity mediated by DRA.
cystic fibrosis transmembrane conductance regulator; cystic fibrosis; trachea; bicarbonate secretion; downregulated in adenoma; chloride ion/bicarbonate exchange
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